Noninvasive measurement of oxygen tension in the optic nerve head

Understanding the pathophysiology of the optic nerve head (ONH) requires precise knowledge of the oxygenation of this tissue. Previous investigations used methods based on oxygen sensitive microelectrodes to measure the partial pressure of oxygen in the ONH tissue. These microelectrodes are inserted into the eye through the pars plana. New methods are now being developed to measure the intravascular PO2 in the ONH. They are based on the quenching of phosphorescence of a porphyrin dye by oxygen. Although these methods require an intravenous injection of this dye, the eye is left untouched. This article reviews these noninvasive methods.     

手术降低眼压对视盘参数及视网膜神经纤维层厚度的影响

背景 降眼压治疗是青光眼最确切的治疗手段.明确降眼压治疗对视盘和视网膜神经纤维层厚度(RNFLT)的影响及其随时间而变化的规律将为青光眼患者降眼压治疗效果的评估提供视神经评价的客观依据. 目的 动态评价原发性开角型青光眼(POAG)患者小梁切除手术前后视盘结构参数和RNFLT的改变,分析青光眼患者手术前后的影像结构改变与眼压下降幅度及视野平均缺损(MD)的关系. 方法 采用前瞻性病例系列观察研究设计.纳入在中山大学中山眼科中心接受小梁切除手术治疗的POAG患者39例40眼,术前高眼压状态下及术后2周,1、3、6个月及1年均行眼压测量,并采用海德堡视网膜扫描仪进行视盘形态学检查,采用光学相干断层扫描仪(OCT)进行RNFLT测量,术前及术后3个月、6个月、1年行双眼视野检查.比较手术前后视盘结构参数和RNFLT随时间的变化情况,并分析眼压下降幅度以及疾病严重程度对视盘结构参数改变的影响. 结果 POAG患者39例40眼术前平均眼压为(32.77±8.64) mmHg(1 mmHg=0.133 kPa);术后2周,1、3、6个月,1年的眼压分别为(12.45±3.65)、(13.05±3.90)、(13.42±3.33)、(14.22±2.60)、(14.74±2.46) mmHg,均较术前明显下降,各时间的总体差异有统计学意义(F=13.73,P=0.00),POAG患者术眼手术前后视野MD值的变化差异无统计学意义(F=1.02,P=0.41).小梁切除手术后视盘参数视杯面积(CA)、杯/盘面积比(C/DAR)、视杯容积(CV)、平均视杯深度(MCD)、视杯形态测量(CSM)、水平C/D、垂直C/D比手术前变小,盘沿面积(RA)、沿/盘面积比(R/DAR)、视盘轮廓线高度变化(HVC)、盘沿容积(RV)、平均视网膜神经纤维层厚度(mRNFLT)、视网膜神经纤维层截面面积(RNFLA)比手术前增加,但随着术后时间的延长,改善参数逐渐减少,至术后1年,RV、CSM、mRNFLT、RNFLA仍较术前增加,而垂直C/D较术前减少,差异均有统计学意义(P＜0.05).手术前后各时间点OCT测量的全周mRNFLT和上方、下方、鼻侧、颞侧4个象限mRNFLT比较差异均无统计学意义(F=1.63,P=0.16;F=0.51,P=0.77;F=1.44,P=0.20;F=1.02,P=0.32;F=1.31,P=0.30).术后1年较术前眼压下降的幅度与RV,CSM及垂直C/D的改善幅度均呈正相关(r=0.45,P=0.02;r=0.41,P=0.04;r=0.58,P=0.00).术眼手术前MD绝对值与术后1年RV及CSM的改善幅度均呈负相关(r=-0.43,P=0.03;r=-0.62,P=0.00).结论 小梁手术有效降低眼压后1年,POAG患者的视盘结构参数可部分得到改善,疾病程度越轻,眼压下降的幅度越大,视盘结构参数的改善越明显.     

Displacement of the optic nerve head by acute changes in intraocular pressure in monkey eyes

The authors used the Humphrey Retinal Analyzer to study the effect of acute changes in intraocular pressure (IOP) on the topography of the optic nerve head in normotensive and hypertensive eyes of cynomolgus monkeys. Chronically elevated IOP was produced monocularly in monkeys by argon laser angle treatment. In 8 hypertensive eyes, the mean IOP of 51 mmHg was lowered acutely to 15 mmHg with a needle placed in the anterior chamber. In 12 normotensive eyes, the mean IOP of 16 mmHg was similarly increased to 45 mmHg. Simultaneous stereophotographs were taken both before and within 15 minutes after the IOP change. The surface of normotensive optic nerve heads moved posteriorly a mean of 17.8 microns after IOP elevation (P less than 0.02). The surface of hypertensive optic nerve heads moved anteriorly 47.4 microns after IOP lowering (P = 0.1); this change was significantly less in nerve heads with larger and deeper cups (P less than 0.02). Significant changes were not detected in disc diameter or vein diameter with acute changes in IOP. Measurable shifts in the position of the optic nerve head surface when IOP is altered may provide a future prognostic test for glaucomatous optic neuropathy.     

Time course of changes in optic nerve head circulation after acute reduction in intraocular pressure

PURPOSE: To study the time course of changes in circulation in the optic nerve head (ONH) after acute reduction in intraocular pressure (IOP) and to evaluate the effects of a calcium antagonist, a nitric oxide synthetase (NOS) inhibitor, indomethacin, and sympathetic nerve amputation on the changes in ONH circulation after reduction of IOP. METHODS: In anesthetized albino rabbits, acute reduction of IOP (acute increase in ocular perfusion pressure [OPP]) was manometrically achieved and normalized blur (NB), a quantitative index of tissue blood velocity obtained with the laser speckle method, was serially monitored for 30 seconds and 60 minutes. The effects of systemic administration of 1 microg/kg per hour nilvadipine (a calcium antagonist), 300 microg/kg Nomega-nitro-l-arginine (l-NAME, a nonselective NOS inhibitor), and 5 mg/kg indomethacin or sympathetic nerve amputation on the changes in NB after reduction of IOP were studied. RESULTS: During changes in IOP from 10 to 40 mm Hg and then back to 10 mm Hg, NB exhibited no significant change. During changes in IOP from 10 to 60 mm Hg and then back to 10 mm Hg, NB initially decreased with an increase in IOP to 60 mm Hg and then increased to baseline level when IOP was returned to 10 mm Hg. In the nilvadipine-treated rabbits, during changes in IOP from 10 to 40 mm Hg and back to 10 mm Hg and during the changes from 10 to 60 mm Hg and back to 10 mm Hg, NB decreased with increase in IOP to 40 or 60 mm Hg and then increased to slightly above the baseline when IOP returned to 10 mm Hg. l-NAME, indomethacin, and sympathetic nerve amputation each had little effect on the time course of change in NB. CONCLUSIONS: ONH circulation was stably maintained after reduction of IOP from 40 to 10 mm Hg but not after that from 60 to 10 mm Hg. The changes in NB after reduction of IOP occurred quickly and were partially impaired with a calcium antagonist, but not with the NOS inhibitor, indomethacin, or sympathetic nerve amputation. These findings suggest the importance of vascular smooth muscle in maintaining stable ONH circulation against reduction of IOP in a fashion nearly independent of NO, endogenous prostaglandins, and the sympathetic nervous system.     

Distribution of axonal transport blockade by acute intraocular pressure elevation in the primate optic nerve head.

We studied the degree of axonal transport blockade in various areas of the optic nerve head with acute intraocular pressure (IOP) elevation in 19 squirrel monkey eyes. When IOP was raised to 20 to 50 mm. Hg for 7 hr., mild axonal transport blockade occurred in each area of the disk, most prominently in nerve fiber bundles of the superior pole. With 7 hr. IOP elevations between 50 and 90 mm. Hg, a somewhat greater degree of transport blockade occurred throughout the nerve head, although again the superior and inferior poles were somewhat more affected. The distribution of short-term transport blockade over the entire nerve head corresponds to the diffuse damage of acute glaucoma, but the pattern hints at the preference for damage near the poles of the disk seen in chronic glaucoma. However, before these results can be fully evaluated, further information is needed on axonal pathways through the optic nerve head and on the relationship between transport obstruction and ganglion cell death.     

Intravenous nicardipine in cats increases optic nerve head but not retinal blood flow.

The effect of intravenously injected nicardipine on retinal and optic nerve head (ONH) blood flow was studied in 27 cats using laser Doppler velocimetry and flowmetry, respectively. A dose of 20 micrograms/kg of nicardipine had little effect on retinal blood flow. A dose of 100 micrograms/kg, however, produced a significant transient decrease in flow. By contrast, both doses produced a significant increase in ONH blood flow despite a significant decrease of the mean arterial blood pressure. Measurements of the partial pressure of oxygen (PO2) with an oxygen-sensitive microelectrode, whose tip was placed in the vitreous just in front of the optic disc, showed a significant increase in the PO2 that paralleled the increase in ONH blood flow. These results demonstrate, for the first time to the authors' knowledge, a pharmacologically induced increase in ONH blood flow and suggest that nicardipine could have a beneficial effect on ONH tissue.     

Deformation of the rodent optic nerve head and peripapillary structures during acute intraocular pressure elevation

PURPOSE. To evaluate the effect of acutely elevated intraocular pressure (IOP) on retinal thickness and optic nerve head (ONH) structure in the rat eye by spectral domain-optical coherence tomography (SD-OCT). METHODS. Fourteen adult male Brown-Norway rats were studied under anesthesia (ketamine/xylazine/acepromazine, 55:5:1 mg/kg intramuscularly). Both eyes were imaged by SD-OCT on two baseline occasions several weeks before and again 2 and 4 weeks after the acute IOP imaging session. During the acute IOP session, SD-OCT imaging was performed 10 minutes after IOP was manometrically set at 15 mm Hg and then at 10, 30, and 60 minutes after IOP had been elevated to 50 mm Hg (n = 8) and again 10 and 30 minutes after IOP had been lowered back to 15 mm Hg (recovery). In two additional groups, IOP elevation was set to 70 mm Hg (n = 4) or 40 mm Hg (n = 2). Acute IOP results are reported for a pattern of 49 horizontal B-scans spanning a 20° square and follow-up results for peripapillary circular B-scans. Retinal and retinal nerve fiber layer (RNFL) thicknesses were measured with custom software by manual image segmentation. Friedman and Dunn's tests were used to assess acute and longer-term effects of acute IOP elevation. RESULTS. Acute IOP elevation to 50 mm Hg caused rapid (within seconds) deformation of the ONH and peripapillary structures, including posterior displacement of the ONH surface and outward bowing of peripapillary tissue; retinal thickness decreased progressively from 10 to 30 to 60 minutes by 16%, 18%, and 20% within the area of Bruch's membrane opening (BMO; P < 0.0001) by 8%, 9%, and 11% within the central 10° (excluding the BMO; P < 0.0001) but only by 1%, 2%, and 2.4% beyond the central 10° (P < 0.0001). Recovery was progressive and nearly complete by 30 minutes. Acute IOP elevation to 40 and 70 mm Hg produced similar structural changes, but 70 mm Hg also interfered with retinal blood flow. There were no changes in peripapillary retinal or RNFL thickness (P = 0.08 and P = 0.16, respectively) measured 2 and 4 weeks after acute elevation to 50 mm Hg. CONCLUSIONS. Acute IOP elevation in the rodent eye causes rapid, reversible posterior deformation of the ONH and thinning of the peripapillary retina, with only minimal retinal thinning beyond 5° of the ONH. No permanent changes in peripapillary retinal or RNFL thickness (for up to 1 month of follow-up) were caused by 60 minutes of IOP elevation to 50 mm Hg.     

Optic nerve oxygen tension: effects of intraocular pressure and dorzolamide

AIM: To investigate the influence of acute changes in intraocular pressure on the oxygen tension in the vicinity of the optic nerve head under control conditions and after intravenous administration of 500 mg of the carbonic anhydrase inhibitor dorzolamide. METHODS: Domestic pigs were used as experimental animals. Oxygen tension was measured by means of a polarographic electrode in the vitreous 0.5 mm anterior to the optic disc. This entity is called the optic nerve oxygen tension. Intraocular pressure was controlled by a hypodermic needle inserted into the anterior chamber and connected to a saline reservoir. RESULTS: When the intraocular pressure was clamped at 20 cm H2O optic nerve oxygen tension was 20 (5) mm Hg (n=8). Intravenous administration of dorzolamide caused an increase in optic nerve oxygen tension of 43 (8)% (n=6). Both before and after administration of dorzolamide optic nerve oxygen tension was unaffected by changes in intraocular pressure, as long as this pressure remained below 60 cm H2O. At intraocular pressures of 60 cm H(2)O and below, dorzolamide significantly increased optic nerve oxygen tension. CONCLUSION: Intravenous administration of 500 mg dorzolamide increases the oxygen tension at the optic nerve head during acute increases in intraocular pressure.     

Time course of the change in optic nerve head circulation after an acute increase in intraocular pressure

PURPOSE: To investigate the time course of changes in optic nerve head (ONH) circulation after an acute increase in intraocular pressure (IOP), by using the laser speckle method, and to evaluate the effects of a calcium antagonist, the nitric oxide synthetase inhibitor, indomethacin, or sympathetic nerve amputation on the response in ONH circulation after an acute increase in IOP. METHODS: In rabbits, the normalized blur (NB) level, a quantitative index of tissue blood velocity in the ONH, was monitored for 60 minutes after an increase in IOP from 20 mm Hg to 40, 50, or 60 mm Hg and for 25 seconds after increase in IOP from 20 mm Hg to 50 or 60 mm Hg with high time resolution. The effects of systemic administration of 1 micro g/kg per hour nilvadipine (a calcium antagonist), 30 mg/kg N(omega)-nitro-L-arginine (L-NAME), or 5 mg/kg indomethacin, or those of sympathetic nerve amputation on the time course of the changes in NB were studied. RESULTS: NB showed a quick recovery within several seconds after increase in IOP to 40 or 50 mm Hg, whereas no or little recovery occurred after an increase to 60 mm Hg. The nilvadipine treatment significantly increased NB at IOP of 20 mm Hg (baseline NB, P = 0.045) and apparently impaired the recovery of NB after the increase in IOP. After L-NAME administration, baseline NB significantly decreased (P = 0.028), and the NB recovery time was slightly but significantly prolonged (P = 0.012). Indomethacin showed no effects on baseline NB or NB recovery. Sympathetic nerve amputation increased baseline NB (P = 0.027), but did not influence NB recovery. CONCLUSIONS: The current results showed a quick recovery response in the ONH circulation after an acute increase in IOP in rabbits. A calcium antagonist impaired the response. Production of nitric oxide or prostaglandins or the sympathetic nervous system is probably not mainly responsible for the reaction.     

Chronology of optic nerve head and retinal responses to elevated intraocular pressure

PURPOSE: To determine the chronology of optic nerve head and retinal responses to elevated intraocular pressure (IOP). METHODS: After 1 to 39 days of unilaterally elevated IOP, experimental and fellow rat eyes were examined for morphology and immunohistochemical labeling alterations and for ganglion cell DNA fragmentation. RESULTS: Mean IOP for the experimental eyes was 36 +/- 8 mm Hg, an approximately 15-mm Hg elevation above normal values. By 7 days of pressure elevation above 40 mm Hg, endogenous immunostaining for brain-derived neurotrophic factor and neurotrophin 4/5 was absent from the nerve head and superior retina, whereas normal labeling was present in the inferior retina and distal optic nerve of these same eyes. These changes were preceded by a loss of gap junctional connexin43 labeling and astrocytic proliferation in the nerve head and by increased retinal ganglion cell layer apoptosis in the retina. Nerve head depletion of neurotrophins coincided with evidence of axonal degeneration, loss of astrocytic glial fibrillary acidic protein staining, and spread of collagen VI vascular immunolabeling. After longer durations at these same pressures, neurotrophin labeling returned to nerve head glia and scattered retinal ganglion cells. CONCLUSIONS: Optic nerve head and retinal responses, including the depletion of endogenous neurotrophins, are readily identified in the rat eye after experimental IOP elevation. However, the apparent chronology of these responses suggests that the withdrawal of neurotrophic support was not the only determinant of retinal ganglion cell apoptosis and axonal degeneration in response to pressure.     

Chronic experimental glaucoma in primates. II. Effect of extended intraocular pressure elevation on optic nerve head and axonal transport

Intraocular pressure (IOP) elevations lasting from 2 to 42 days were produced in 13 primate eyes by anterior chamber injections of autologous, fixed red blood cells. The retina, optic nerve head, and optic nerves were studied by electron microscopy, and ganglion cell rapid axonal transport was examined after IOP elevations for various durations. Transport of axonal material was blocked at the scleral lamina cribrosa by IOP elevations to 50 mm Hg. With IOP elevation for less than 1 week, return to normal IOP restored normal transport in some axons. However, in other axons IOP elevation for less than 1 week intiated ganglion cell degeneration. The process of cellular death involved a rapid ascending degeneration from nerve head to brain, followed 3 to 4 weeks later by descending degeneration of the ganglion cell body and its attached axon. Axons of the superior and inferior optic nerve head and nerve seem to be damaged more extensively than those in the nasal and temporal optic nerve. Two to four days after IOP elevation, axons of the superficial optic nerve head were swollen with accumulating axonal material, leading to histologic disk edema. In those eyes with IOP elevation longer than 1 week, the loss of anterior disk nerve fibers combined with posterior and lateral movement of the lamina cribrosa lead to an increase in optic disk cupping. Astrocytes and capillaries of the optic nerve head seem to tolerate elevated IOP well and were relatively spared.     

Breakdown of the normal optic nerve head blood-brain barrier following acute elevation of intraocular pressure in experimental animals

Five hours of elevated intraocular pressure produced evidence of an altered blood-brain barrier at the optic nerve head in 27 of 29 monkey eyes. The change in vascular permeability was documented by fluorescein angiography (18 of 21 eyes), by Evans blue fluorescence microscopy (21 of 23 eyes), or by both methods. Leakage occurred from major blood vessels as well as from microvasculature of the nerve head. In 22 eyes, rapid axonal transport was studied after intravitreal injection of tritiated leucine. In 18 of these 22 eyes, autoradiography demonstrated a local interruption of axonal transport. In 15 eyes examined by all three methods, leakage from microvasculature (as opposed to leakage from the major vessels) was loosely associated with severe and widespread blockade of axonal transport at the lamina cribrosa. Although cause-and-effect relationships are not proved, ischemia may be responsible both for the focal endothelial damage with breakdown of the normal blood-brain barrier and for the local abnormalities of axonal transport.     

The mechanism of optic nerve damage in experimental acute intraocular pressure elevation

We produced intraocular pressure (IOP) elevations in 32 primate eyes and studied retinal ganglion cell rapid axonal transport with autoradiography and electron microscopy. Animals breathing room air at sea level pressure were compared to animals breathing 100% oxygen at 3 atm pressure in a hyperbaric chamber. Despite major increases in arterial oxygen levels in the hyperbarically oxygenated animals, both groups had axonal transport blockade at the optic nerve head. Anoxia appears not to be the most important cause of acute axonal damage induced by elevated IOP. The pattern of axonal abnormality within individual fiber bundles at the optic nerve head provides support for mechanical compression as a more likely alternative cause for induced neural damage.     

The acute morphologic changes that occur at the optic nerve head induced by medical reduction of intraocular pressure

PURPOSE: The mechanical theory of glaucoma postulates that raised intraocular pressure (IOP) causes laminar distortion resulting in damage to axons at the optic nerve head. There is some evidence that the change in morphology may occur over a short time course. The aim of this paper was to detail the acute morphologic changes at the optic nerve head when IOP was lowered with medical therapy in a clinical population. METHODS: Subjects referred to the glaucoma clinic that had a documented IOP of over 28 mm Hg, on no treatment, in one or both eyes were included. Tonometry, pachymetry, and scanning laser ophthalmoscopy were performed before and after lowering IOP with topical apraclonidine and oral acetazolamide. The significance of change in outcome variables was assessed using a paired t test allowing for dependence within subjects and, for sensitivity, with a nonparametric Wilcoxon signed-rank test. RESULTS: Data were obtained from 38 eyes of 19 patients with a mean age of 67 years. After lowering IOP for only 1 hour, there was a significant decrease in mean cup volume (mean change in volume below surface 26.8 microm3, P< or =0.001) and mean cup depth (13.8 microm, P<0.01), there being a corresponding increase in mean rim area (37.3 microm2, P<0.034). There was no statistically significant change in central corneal thickness after administration of the IOP lowering medications. CONCLUSIONS: In the present study, it was shown that acute and statistically significant alterations in optic disc morphology occur when IOP is lowered medically with a combination of topical apraclonidine and systemic acetazolamide. The technique, therefore, may be useful to further investigate subgroups of glaucomatous eyes and test etiologic hypotheses.     

Factors associated with topographic changes of the optic nerve head induced by acute intraocular pressure reduction in glaucoma patients

Purpose

To investigate factors associated with changes in optic nerve head (ONH) topography after acute intraocular pressure (IOP) reduction in patients with primary open-angle glaucoma (POAG).

Methods

Untreated POAG patients (IOP >21 mm Hg) were prospectively enrolled. Systemic and ocular information were collected, including central corneal thickness (CCT) and corneal hysteresis (CH). All patients underwent confocal scanning laser ophthalmoscopy and tonometry (Goldmann) before and 1 h after pharmacological IOP reduction. The mean of three measurements was considered for analysis. Changes in each ONH topographic parameter were assessed (one eye was randomly selected), and those that changed significantly were correlated with patient''s systemic and ocular characteristics.

Results

A total of 42 patients were included (mean age, 66.7±11.8 years). After a mean IOP reduction of 47.3±11.9%, significant changes were observed in cup area and volume, and in rim area and volume (P<0.01), but not in mean cup depth (P=0.80). Multiple regression analysis (controlling for baseline IOP and magnitude of IOP reduction) showed that CH (r²=0.17, P<0.01) and diabetes diagnosis (r²⩾0.21, P<0.01) were negatively correlated with the magnitude of changes in ONH parameters, whereas the cup-to-disc ratio was positively correlated (r²=0.30, P<0.01). Age, race, disc area, and CCT were not significant (P⩾0.12). Including all significant factors in a multivariable model, only the presence of diabetes remained significantly associated with all ONH parameters evaluated (P<0.01).

Conclusions

Different systemic and ocular factors, such as diabetes, CH, and the relative size of the cup, seem to be associated with the magnitude of changes in ONH topography after acute IOP reduction in POAG patients. These associations partially explain the ONH changes observed in these patients and suggest that other factors are possibly implicated in an individual susceptibility to IOP.